Field of the Invention
This invention generally relates to the field of acid-degradable and bioerodible materials and polymers for use in delivery of bioactive materials such as antigens, DNA and other therapeutics or as bulk materials such as sutures, scaffolds, and implants.
Description of the Related Art
Polyesters, polyorthoesters, and polyanhydrides are widely used materials for biomedical applications due to their biodegradability, biocompatibility and processability (Yolles, S.; Leafe, T. D.; Meyer, F. J., J. Pharm. Sci. 1975, 64, 115-6; Heller, J., Ann. N. Y. Acad. Sci. 1985, 446, 51-66; Rosen, H. B.; Chang, J.; Wnek, G. E.; Linhardt, R. J.; Langer, R., Biomaterials 1983, 4, 131-3). Microparticles made from these polymers have been used as carriers for vaccine applications, gene delivery and chemotherapeutic agents. (Solbrig, C. M.; Saucier-Sawyer, J. K.; Cody, V.; Saltzman, W. M.; Hanlon, D. J., Mol. Pharm. 2007, 4, 47-57; Gvili, K.; Benny, O.; Danino, D.; Machluf, M., Biopolymers 2007, 85, 379-91; Sengupta, S.; Eavarone, D.; Capila, I.; Zhao, G. L.; Watson, N.; Kiziltepe, T.; Sasisekharan, R., Nature 2005, 436, 568-572). The encapsulated cargo is typically released over the course of several months via surface erosion and the slow degradation of the polymer. (Matsumoto, A.; Matsukawa, Y.; Suzuki, T.; Yoshino, H., J. Control Release 2005, 106, 172-80).
For many drug delivery applications, it is desirable to release therapeutic agents under mildly acidic conditions, which can be found for example in sites of inflammation, lysosomal compartments, or tumor tissue. ((a) Sun-Wada, G. H.; Wada, Y.; Futai, M., Cell Struct. Funct. 2003, 28, 455-63 (b) Helmlinger, G.; Sckell, A.; Dellian, M.; Forbes, N. S.; Jain, R. K., Clin. Cancer Res. 2002, 8, 1284-91) Acid-sensitive liposomes, micelles and hydrogels ((a) Sawant, R. M.; Hurley, J. P.; Salmaso, S.; Kale, A.; Tolcheva, E.; Levchenko, T. S.; Torchilin, V. P., Bioconjug Chem 2006, 17, 943-9 (b) Mandracchia, D.; Pitarresi, G.; Palumbo, F. S.; Carlisi, B.; Giammona, G., Biomacromolecules 2004, 5, 1973-82 (c) Murthy, N.; Thng, Y. X.; Schuck, S.; Xu, M. C.; Frechet, J. M. J., J. Am. Chem. Soc. 2002, 124, 12398-12399) have previously been developed, but few easily-prepared polymeric materials exist that combine acid-sensitivity and biodegradability.
Poly(β-amino esters), which are protonated and thus become soluble at lower pH (Little, S. R.; Lynn, D. M.; Ge, Q.; Anderson, D. G.; Puram, S. V.; Chen, J.; Eisen, H. N.; Langer, R., Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 9534-9), constitute one such material. However, these polymers become polycationic under acidic conditions and must be blended with biocompatible polyesters to reduce their toxicity (Little, S. R.; Lynn, D. M.; Puram, S. V.; Langer, R., J. Control Release 2005, 107, 449-62).
Currently there is no system with the flexibility and biocompatibility of polyester materials, but with the additional benefit of a change in rate of payload release that is sensitive to physiologically relevant acidic conditions.